The research proposed is related to two of the most common inherited hemoglobinopathies in humans, beta thalassemia and sickle cell disease. Beta thalassemia is characterized by an absence or a reduction in the amount of the beta-globin chains, whereas in sickle cell anemia there is a single amino acid substitution in the beta-globin chain. These diseases cause considerable mortality and morbidity in humans. Naturally occurring mouse models of beta+ thalassemia have ben found by Skow et al. (1983) and an additional mouse model of beta+ thalassemia has been generated by gene targeting in this laboratory by Shehee et al. (1993). No models are available for beta+ thalassemia, a condition which resembles the most severe form of Cooley's anemia. Current genetic models for sickle cell disease are unsatisfactory because of the persistence of endogenous globin synthesis in the animals. I propose to use gene targeting to generate mice that are unable to synthesize any adult beta-globin, and which will therefore serve as models for Cooley's anemia. I also propose to replace both mouse adult alpha- and beta-globin genes with the corresponding human genes and thereby generate a mouse model in which mouse adult hemoglobins will be completely replaced by human sickle hemoglobin. These two models will not only enrich our knowledge about these two diseases, but should also be of great value in developing better treatment modalities for the two disease particularly those based on gene therapy.